Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Semin Cancer Biol. 2020 Dec;67(Pt 2):159-170. doi: 10.1016/j.semcancer.2020.01.012. Epub 2020 Jan 30.
D cyclins include three isoforms: D1, D2, and D3. D cyclins heterodimerize with cyclin-dependent kinase 4/6 (CDK4/6) to form kinase complexes that can phosphorylate and inactivate Rb. Inactivation of Rb triggers the activation of E2F transcription factors, which in turn regulate the expression of genes whose products drive cell cycle progression. Because D-type cyclins function as mitogenic sensors that link growth factor signaling directly with G phase progression, it is not surprising that D cyclin accumulation is dysregulated in a variety of human tumors. Elevated expression of D cyclins results from gene amplification, increased gene transcription and protein translation, decreased microRNA levels, and inefficiency or loss of ubiquitylation-mediated protein degradation. This review focuses on the clinicopathological importance of D cyclins, how dysregulation of Ubiquitin-Proteasome System (UPS) contributes to the overexpression of D cyclins, and the therapeutic potential through targeting D cyclin-related machinery in human tumors.
D 型细胞周期蛋白包括三种同工型：D1、D2 和 D3。D 型细胞周期蛋白与细胞周期蛋白依赖性激酶 4/6（CDK4/6）异二聚化形成激酶复合物，可磷酸化并失活 Rb。Rb 的失活触发 E2F 转录因子的激活，反过来又调节其产物驱动细胞周期进程的基因的表达。由于 D 型细胞周期蛋白作为有丝分裂原传感器，将生长因子信号直接与 G1 期进展联系起来，因此 D 型细胞周期蛋白在各种人类肿瘤中的失调并不奇怪。D 型细胞周期蛋白的表达升高是由于基因扩增、基因转录和蛋白翻译增加、miRNA 水平降低以及泛素-蛋白酶体系统（UPS）效率降低或丧失导致的蛋白降解。这篇综述重点介绍了 D 型细胞周期蛋白的临床病理重要性，UPS 失调如何导致 D 型细胞周期蛋白的过度表达，以及通过靶向人类肿瘤中与 D 型细胞周期蛋白相关的机制来治疗的潜力。
